GASTROINTESTINAL

“We’ve seen an explosion of immunotherapy in the last decade, with the greatest success in [patients with] stage IV forms of melanoma or non–small cell lung cancer. [However], that success has not yet reached GI cancers… What we did was use CRISPR-Cas9–based gene editing as a tool to delete that gene from inside the cell and therefore offset the checkpoint, to allow the immune system to be retrained—rebooted, in essence—to go against the cancer in patients with metastatic GI cancer.”

Emil Lou, MD, PhD, FACP, an associate professor of medicine in the Division of Hematology, Oncology, and Transplantation at the University of Minnesota Medical School and a medical oncologist at M Health Fairview Masonic Cancer Clinic, discussed the rationale for the first-in-human, single-center phase 1 trial (NCT04426669) evaluating cytokine-inducible SH2-containing protein (CISH) knockout tumor-infiltrating lymphocytes (TILs) using CRISPR-Cas9 gene editing in patients with metastatic gastrointestinal (GI) cancers. This study was designed to investigate whether deletion of 

, an intracellular immune checkpoint regulator, could enhance TIL activity and overcome resistance to immune checkpoint inhibitors in this population.

Lou explained that despite the broad expansion of immunotherapy across solid tumors, clinical success has remained largely confined to melanoma and non–small cell lung cancer. In contrast, GI cancers—particularly metastatic colorectal cancer (mCRC)—continue to demonstrate limited responsiveness to checkpoint blockade, with few durable remissions outside of microsatellite instability–high disease. Given that approximately 150,000 CRC cases are diagnosed annually in the US, including a rising proportion among younger adults, novel immunotherapeutic strategies are urgently needed for patients with metastatic disease, who currently experience median overall survival durations of only 20 to 30 months with standard-of-care chemotherapy.

Unlike conventional checkpoint inhibitors that target extracellular receptors such as PD-1 or CTLA-4, CISH functions intracellularly as a suppressor of T-cell activation and cytokine signaling. Lou and colleagues hypothesized that CRISPR-Cas9–mediated deletion of CISHwould remove this intracellular brake on immune function, thereby restoring and amplifying T-cell cytotoxicity against tumor cells. The CISHknockout strategy aims to reprogram TILs for enhanced persistence, cytokine secretion, and tumor-specific activity within the immunosuppressive tumor microenvironment that characterizes advanced GI malignancies.

According to Lou, this approach represents a mechanistic evolution in cancer immunotherapy, shifting from extracellular checkpoint blockade to intracellular immune engineering. By disrupting CISH, investigators seek to reinvigorate exhausted T cells and enable sustained antitumor activity that conventional antibody-based checkpoint inhibitors cannot achieve. The ongoing phase 1 study will evaluate the safety, feasibility, and preliminary efficacy of this CRISPR-based TIL therapy, with the broader goal of establishing proof-of-concept for intracellular checkpoint modulation as a next-generation immunotherapeutic strategy for patients with GI cancers resistant to standard immunotherapy approaches, he concluded.

Videos

Emil Lou, MD, PhD, FACP, discusses the rationale for evaluating CISH knockout TILs using CRISPR-Cas9 gene editing in metastatic GI cancers.

Dr Lou on the Rationale for Evaluating CISH Knockout TILs Using CRISPR-Cas9 Gene Editing in Metastatic GI Cancers

Dr Lou on the Predictive and Prognostic Utility of Tumor Stroma Proportion in Ovarian Cancer

Emil Lou, MD, PhD, FACP, medical oncologist, neuro-oncologist, gastrointestinal oncologist, associate professor of medicine, Division of Hematology, Oncology, and Transplantation, University of Minnesota Medical School, discusses the predictive and prognostic value of tumor stroma proportion (TSP) for patient survival outcomes and chemoresistance in ovarian cancer, according to retrospective study.

Investigators conducted this confirmatory prognostic study which built upon prior research indicating the predictive and prognostic value of TSP in ovarian cancer, and aimed to determine whether patients with a higher TSP spent less time on chemotherapy due to the development of chemoresistance, Lou begins.

 indicated that TSP is a consistent and reproducible marker for survival outcomes and resistance to standard platinum-based chemotherapy in high-grade serous ovarian cancer, he reports. In the Tübingen cohort (n = 192), higher TSP levels were linked to increased resistance to platinum-based chemotherapy, accompanied by shorter progression-free survival (PFS; HR, 1.586; 95% CI, 1.093-2.302; 

 = .02) and overall survival (OS; HR, 1.867; 1.249-2.789; 

 = .002). However, no significant correlations were observed between TSP levels and chemoresistance, PFS, or OS in The Cancer Genome Atlas cohort (n = 103). Notably, patients with chemoresistant tumors were twice as likely to exhibit high TSP vs those with chemosensitive tumors (HR, 2.861; 95% CI, 1.256-6.515; 

These findings are consistent with prior research conducted by Lou and colleagues, confirming a statistically significant association between lower TSP levels and worse OS, in addition to heightened chemoresistance. Overall, patients with high TSP experienced a shorter duration of effective chemotherapy before disease progression or recurrence, Lou reiterates.

The study supports the use of TSP as a predictive biomarker strongly correlated with chemoresistance and prognostic marker of poorer outcomes in ovarian cancer patients, he emphasizes. Further validation and integration of TSP into routine clinical care could ultimately help identify patients with ovarian cancer who are most likely to benefit from standard treatments, Lou concludes.

Emil Lou, MD, PhD, FACP, discusses the predictive and prognostic value of tumor stroma proportion for survival outcomes in ovarian cancer.

Emil Lou, MD, PhD, FACP

Articles

Dr Lou on the Rationale for Evaluating CISH Knockout TILs Using CRISPR-Cas9 Gene Editing in Metastatic GI Cancers

Dr Lou on the Predictive and Prognostic Utility of Tumor Stroma Proportion in Ovarian Cancer